tbuckley/cabot-search huggingface dataset:
EPCO-19. TUMOR-WIDE NEOANTIGEN-SPECIFIC T-CELLS INFILTRATING MUTANT IDH1 LOW-GRADE GLIOMAS AND PERSISTING IN PERIPHERAL BLOOD ALLOW FOR PERSONALIZED TCR-BASED IMMUNOTHERAPIES
Authors: Darwin Kwok, Michael Zhang, Cliff Wang, Nicholas Stevers, Tyler Borrman, Zheng Pan, Benjamin Yuen, Songming Peng, Diana Nguyen, Michael Martin, Chibo Hong, Stephanie Hilz, Joanna Phillips, Anny Shai, Nancy Ann Oberheim Bush, Shawn Hervey-Jumper, Michael McDermott, Stefanie Mandl, Hideho Okada, Joseph Costello
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The low mutational burden and immunologically “cold” microenvironment of mutant IDH1 low-grade gliomas (LGG) are considerable challenges in immunotherapy for these tumor types. However, we hypothesize that LGG-targeting T-cells may exist at low frequency and with limited regional infiltration within the tumor. Through multi-region tumor sampling coupled with high-throughput T-cell receptor (TCR) profiling, we identified tumor-wide neoantigens and corresponding neoantigen-specific T-cells regionally infiltrating the tumor and persisting in peripheral blood. METHODS Maximally-distanced anatomical sampling of at least 10 distinct tumor regions was performed at the initial resection for three WHO Grade II diffuse astrocytoma patients for exome-based prediction of clonally and subclonally expressed neoantigens, RNAseq analysis of regional immune cell composition, and TCR beta deep sequencing. We used these predictions to generate a barcoded library of patient-specific peptide-HLA multimers loaded with predicted neoepitopes. With this library, neoantigen-specific CD8+ T-cells were captured and isolated from patients’ peripheral blood. Single-cell TCR sequencing allowed us to identify the neoantigen-reactive TCR clonotypes which were transduced subsequently into Jurkat76 cell lines for functional validation. RESULTS We screened patient-derived peripheral blood drawn two years after initial resection in 3 mutant IDH1 LGG patients and detected a total of 20 TCR clonotypes recognizing neoepitopes derived from truncal, tumor-wide mutations in CNTNAP1 (n=8), TP53 (n=3), and MRPL46 (n=2) as well as subclonal mutations in PRMT5 (n=1) and ZDHHC5 (n=6). Jurkat76 cells transduced with the mutant-PRMT5-specific TCR demonstrated dose-dependent neoantigen-specific immune responses when co-cultured with mutant-PRMT5 pulsed-antigen presenting cells expressing HLA-A*0201. CONCLUSION Our study demonstrates the existence and persistence of neoantigen-targeting T-cells within the blood and tumor of mutant IDH1 LGG patients. We identified a TCR clonotype that successfully recognizes and induces an immune response against mutant-PRMT5. These findings suggest a feasible methodology to develop personalized T-cell-based immunotherapies for patients with mutant IDH1 LGGs.
EXTH-09. GM-CSF AND IL-7 FUSION CYTOKINE ENGINEERED TUMOR VACCINE GENERATES LONG-TERMTH-17 MEMORY CELLS AND INCREASES OVERALL SURVIVAL IN AGED SYNGENEIC MOUSE MODELS OF GLIOBLASTOMA
Authors: Jack Shireman, Nikita Gonugunta, Akshita Pattnaik, Lei Zhao, Xiaohu Wang, Jacques Galipeau, Mahua Dey
Journal: Neuro-Oncology (2023)

Abstract Age-related immune dysfunctions, such as decreased T-cell output, are closely related to pathologies like cancers and lack of vaccine efficacy among the elderly. Engineered fusokine, GIFT-7, a fusion of IL-7 and GM-CSF, can reverse aging-related lymphoid organ atrophy. We generated a GIFT-7 fusokine tumor vaccine and employed it in aged syngeneic mouse models of glioblastoma, and found that peripheral vaccination with GIFT-7TVax resulted in thymic regeneration and generated durable long-term anti-tumor immunity specifically in aged mice. Global cytokine analysis showed increased pro-inflammatory cytokines including IL-1b in the vaccinated group that resulted in hyperactivation of dendritic cells. In addition, GIFT-7 vaccination resulted in increased T-cell trafficking to the brain and robust Th-17 long-term effector memory T-cell formation. TCR-seq analysis showed increased productive frequency among detected rearrangements within the vaccinated group. Overall, our data demonstrate that aging immune system can be therapeutically augmented to generate lasting anti-tumor immunity.
EPCO-01. THE GENOMIC LANDSCAPE OF BRAIN METASTASIS
Authors: Anna Skakodub, Henry Walch, Rahul Kumar, Jordan Eichholz, Claire Cooper, Ishaani Khatri, Luke Del Balzo, Emily Miao, Chengcheng Gui, Jennifer Ma, Kathryn Tringale, Benjamin Gaeta, Daniel Kelly, Nelson Moss, Kenny Kwok Hei Yu, Jessica Wilcox, Tejus Bale, Yao Yu, Yoshiya Yamada, Brandon Imber, Daniel Gomez, Nikolaus Schultz, Luke Pike
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The prognosis for patients with brain metastasis (BM) is devastating, while the underlying biology of BM development remains poorly understood. Identification of genomic biomarkers can offer promising opportunities for prediction of BM development and guidance in personalized treatment. In this study we evaluate the genomic alterations present in a large cohort of resected BM. METHODS Upon retrospective review, we identified 868 patients with diagnosis of solid primary cancers who had undergone a standard of care craniotomy at Memorial Sloan Kettering Cancer Center (MSKCC). BM samples were profiled by MSK-IMPACT, a next-generation sequencing (NGS) assay designed to detect a wide range of genetic alterations in 341-505 cancer genes. Genomic alterations were filtered for driver variants using OncoKB. Disease sites included cancers of head and neck, breast, lung, lower and upper gastrointestinal tract, kidney, ovary, uterus, prostate, skin, soft tissues, and others. RESULTS More than half (57%; 493/868) of patients were female and the median age was 63 (range 22-93). Foreseeably, the most common histology was non-small cell lung cancer (NSCLC; 38%), followed by invasive carcinoma of the breast and melanoma (16% and 13%, respectively). The most frequently encountered alterations were inTP53 (60%), CDKN2A (25%), TERT (23%), KRAS (18%), and PTEN (12%) across all BM samples. The median fraction of genome altered was 0.41 [range: 0-0.99] and the median tumor mutational burden was 6.6 muts/Mb [range: 0-395]. Additionally, TP53 was the most frequently altered gene after stratifying by primary histology in most cancer types, except for melanoma, renal, and thyroid, which were enriched for alterations in TERT, CDKN2A, and TERT, respectively. CONCLUSION The landscape of genomic alterations present in BM is distinct and varies by primary histologic diagnosis. Ongoing analyses of matched primary-BM pairs and clinicogenomic correlation will identify factors predisposing patients to BM development and progression.
TMIC-69. TARGETING TUMOR-ASSOCIATED MACROPHAGES IN THE IMMUNE-MICROENVIRONMENT OF MENINGIOMAS
Authors: Catharina Lotsch, Rolf Warta, Philip Dao Trong, Andreas Unterberg, Christel Herold-Mende
Journal: Neuro-Oncology (2023)

Abstract Meningiomas represent the most common primary brain malignancies in adults with a subset of tumors exhibiting aggressive clinical behavior. Immunotherapy might present a new treatment strategy but is highly dependent on the immunological composition of the tumor microenvironment. Our previous data have shown that tumor-associated macrophages (TAMs) make up the main immune cell population in meningiomas with a significant negative impact on patient outcome. In this study, we investigated whether TAMs from meningioma tissue could be reprogrammed to an immunologically active and tumoricidal phenotype. For this purpose, CD11b+ sorted macrophages derived from &amp;gt; 40 patients were treated with small molecule inhibitors targeting the colony-stimulating factor-1 receptor (CSF-1R). In a first analysis, the direct treatment response of CD11b+ patient-derived macrophages was investigated by various techniques including flow cytometry and bulk RNA-sequencing of treated TAMs and further analysis of the macrophage-conditioned media after treatment. In addition, we studied the influence of CSF-1R-targeted macrophage treatment on the phenotype and functional activity of T cells to assess a potential indirect treatment response in the tumor microenvironment. Our data revealed that CSF-1R-targeted treatment of CD11b+ TAMs induced significant changes in the protein and gene expression of macrophage polarization markers towards a more immunologically active state and a significantly higher metabolic nitric oxide production as another sign of immunological activation. Subsequent analysis of indirect effects on T cells showed not only a significantly increased expression of the T cell activation marker CD69+, but also a significantly increased tumor cell killing by autologous T cells after macrophage-targeted treatment. Together these data suggest both a direct and indirect CSF-1R-targeted macrophage treatment response in the local tumor microenvironment and give first promising results on the efficacy of macrophage-targeted immunotherapy in human meningiomas.
EXTH-22. AN IND-ENABLED STUDY USING A NOVEL CHECKPOINT BLOCKADE OF LAIR1 FOR GLIOBLASTOMA THERAPY
Authors: Haipeng Tao, Dongjiang Chen, Changlin Yang, Duy Nguyen, Alfonso Pepe, Diego Pedro, Linchun Jin, Ruixuan Liu, Tianyi Liu, Christina Von Roemeling, Muhammad Abbas, Alicia Y Hou, Nicole Petit, Georges Abboud, Hector Mendez-Gomez, Frances Weidert, Dan Jin, Kaytora Long-James, Elias Sayour, Loic Deleyrolle, W Gregory Sawyer, Duane Mitchell, Jianping Huang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Our research study focuses on the recently discovered immune checkpoint known as Leukocyte-Associated Immunoglobulin-like Receptor 1 (LAIR1), which is found to be overexpressed on tumor-associated myeloid cells (MAMC), including Tumor-associated macrophages (TAM) and Myeloid-derived suppressive cells (MDSC), in GBM and other solid cancers. The overexpression of LAIR1 in gliomas is associated with poor survival, which has prompted investigations into the potential of LAIR1 blockade (aLAIR1) as a therapeutic strategy. In preclinical mouse models, Objective: A) To investigate the mechanism of LAIR1, a new class of immune checkpoint. B) To develop strategies for blocking LAIR1 signaling as a means of cancer therapeutics, thereby enabling novel mono and combinatorial treatments for GBM. METHODS 1) Conduct coculture experiments using human TAMs and autologous CAR T cells in a 3D microgel bio-printing system, which allows us to recreate TME using patient-derived immune cells and a heterogeneous glioma model. By monitoring this coculture system, we aim to gain insights into the inhibitory effects of TAMs on T cells mediated by LAIR1. 2) Utilize tumor-burden wild-type and LAIR1 knockout mice to compare the intratumoral immune cell infiltration between WT and KO mice. 3) Employ sc-RNA-seq to identify key molecules involved in the TAM-T cell interaction. 4) Perform pathway analysis to identify signaling pathways that are influenced by this interaction. RESULTS aLAIR1 shifted macrophage polarization from M1 to M2 and increased memory CD8+ T cells intratumorally. It reversed MDSC- or M2- macrophage-mediated T-cell suppression, resulting in enhanced antitumor response as a standalone treatment and when used in combination with CAR T cell therapy in PD-1-resistant tumor models. CONCLUSIONS LAIR1 is a newly identified innate immune checkpoint that is highly expressed on TAMC in solid tumors, contributing to tumor progression and drug resistance. Blocking the LAIR1 signaling pathway shows promise as an effective approach for cancer therapy.
PATH-32. COMPARISON OF CLINICAL, RADIOGRAPHIC AND TUMOR GENOMIC ALTERATIONS BETWEEN CLASSIC AND MOLECULAR GLIOBLASTOMA (IDH WILDTYPE)
Authors: Daniel Lachance, Paul Decker, Thomas Kollmeyer, Corinne Praska, Matthew Kosel, Lateef Odukoya, Cristine Ida, Kristen Drucker, Arijit Panda, Gian Marco Conte, Mana Moassefi, W Oliver Tobin, Bradley Erickson, Evanthia Galanis, Jeanette Eckel-Passow, Robert Jenkins
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Prior to 2021, (classic) glioblastoma (GBM) required absence of IDH mutation and histologic features of hypercellularity, nuclear atypia, microvascular proliferation (MVP), and necrosis. Absence of histologic features can be a result of undersampling, with molecular, radiologic, and clinical features consistent with GBM. Accordingly, WHO 2021 defined molecular glioblastoma as diffuse glioma IDHwt, H3wt, with one or more of MVP, necrosis, TERT promoter mutation, EGFR gene amplification (EGFRamp), and/or +7/−10. We hypothesized that there is clinical and radiographic heterogeneity among tumors defined as molecular GBM. METHODS We identified 121 patients that met the criteria for molecular GBM. 121 Classic GBM, defined as IDHwt with hypercellularity, MVP or necrosis, were matched to molecular GBM cases by age, sex, and diagnosis date. All cases were reviewed for relevant histologic features and molecular features. Examined clinical variables included: first symptom, time from first symptom to date of pathological diagnosis, date of first MRI, tumor location, radiographic features of enhancement, diffusion or mass effect, time to progression and overall survival. Clinical, radiologic, and molecular features were compared between classic and molecular GBM. RESULTS Currently,160 cases have been reviewed. Preliminary results show that there is a longer time from first symptom to diagnosis for molecular GBM. Molecular GBM is significantly more likely to be discovered coincidentally, and without enhancement or radiographic necrosis. Classic GBM is significantly more likely to present with focal neurologic deficit as first symptom, regional mass effect on index imaging and have monosomy 10. CONCLUSION While pathologic undersampling accounts for a significant proportion of molecular GBM, our data suggest that there are significant clinical, radiographic, and outcome differences between classical and molecular GBM. Final analysis of the entire cohort will help better define this clinical spectrum.
DDDR-09. FUNCTIONAL GENOMICS AND CHEMOTHERAPY RESISTANCE SCREENING IDENTIFIES BIOMARKERS AND TARGETABLE MECHANISMS OF CCNU RESISTANCE IN GLIOMAS
Authors: Cynthia Hajal, Simona Dalin, Greg Raskind, Margaret Cusick, Seth Malinowski, Jakob Ito, Connor Bossi, Jayne Vogelzang, Charlotte Bellamy, Lisa Salhi, Franck Bielle, Gad Getz, Pratiti Bandopadhayay, Mehdi Touat, Rameen Beroukhim, Keith Ligon
Journal: Neuro-Oncology (2023)

Abstract The bifunctional alkylator lomustine (CCNU) remains widely but heterogeneously used as one of the few effective treatments in glioblastoma (GBM) and IDH mutant gliomas. Despite its widespread use, mechanisms of response and resistance to this agent are controversial and patients who benefit are poorly understood. To address this with next-generation patient models and functional genomics approaches, we generated and characterized CCNU response in a large cohort of 71 patient-derived glioma cell lines (PDCLs, spheroids/organoids). Models had fully defined clinical and molecular characteristics (WES, RNAseq, and patient and model MGMT). Patient models, including those derived from patients who acquired resistance to CCNU, exhibited a surprisingly wide range of differential response to CCNU (median IC50: 21.66uM; range: 1.52uM-159uM) using metabolic (CTG) as well as cell death readouts, with no lines showing complete resistance (EC100 &amp;lt; 291uM). MGMT promoter methylation status but not mismatch repair (MMR) trended, but did not reach, statistical significance as a predictor of CCNU sensitivity (p=0.053), in striking contrast to TMZ (p=0.01). Chronic CCNU exposure of two PDCLs led to acquired resistance to CCNU (IC50 increase from 5uM to 50uM on average). RNA sequencing showed 194 significantly differentially expressed genes while no mutations acquired in resistant models were identified in DNA sequencing. PRISM pooled screening of over 900 barcoded cancer cell lines and correlation with DepMap whole genome CRISPR-knockout data showed unique patterns of CCNU response and strong upregulation of DNA repair targets in the resistant state, which differed from TMZ. Shared targets were also identified in a CRISPR-activator screen performed on a CCNU sensitive cell line in the presence and absence of CCNU and converged on multiple mTOR pathway genes as top enriched targets and biomarkers of resistance in CCNU-resistant models. These druggable targets are currently being investigated for combination therapies with CCNU and potential to overcome resistance.
BIOM-21. LIQUID BIOPSY IN SERA OF HIGH-GRADE GLIOMA PATIENTS: PROTOPORPHYRIN IX AS A BIOMARKER
Authors: Anna Walke, Christopher Krone, Walter Stummer, Simone König, Eric Suero Molina
Journal: Neuro-Oncology (2023)

Abstract High-grade gliomas (HGG) carry a dismal prognosis. Diagnosis comprises magnetic resonance imaging (MRI) followed by histopathological evaluation of tumor tissue after biopsy collection; no blood biomarker is currently available. Patients are subjected to repeated surgery and MRI for relapse monitoring. Protoporphyrin IX (PpIX) is already in routine use for selectively visualizing HGG tissue during fluorescence-guided resection (FGR). We investigated if it can also serve as serum HGG marker. Patients (HGG: n = 23 primary, pHGG; n = 5 recurrent, rHGG) undergoing FGR received 5-aminolevulinic acid (5-ALA) following standard clinical procedure. The control group of eight healthy volunteers (HCTR) also received 5-ALA. Serum was collected before and repeatedly up to 72 h after drug administration. PpIX was analyzed following liquid-liquid and solid-phase extraction using liquid chromatography coupled to ion trap mass spectrometry. The serum PpIX level before 5-ALA administration was similar in patient and control groups. Significant PpIX accumulation in HGG was observed after 5-ALA administration (ANOVA: p = 0.005, post-hoc: HCTR vs. pHGG p = 0.029, HCTR vs. rHGG p = 0.006). Separation of HCTR from pHGG was possible within CI95% of tMax (AUC: 0.943, CI95% 0.884 - 1.000, p &amp;lt; 0.001); the optimal cut-off for diagnosis was 1275 pmol PpIX/ml serum, reaching 87.0 % accuracy, 90.5 % positive predictive value and 84.0 % negative predictive value. Distinguishing pHGG patients from healthy controls based on serum PpIX is possible. The prodrug 5-ALA is required for PpIX induction, which is safe for the standard clinical dosage. Thus, PpIX is a new target for liquid biopsy in glioma, but larger clinical studies are required to characterize its full potential.
CTNI-33. TARGET TRIAL: A PHASE I/II OPEN-LABEL MULTICENTER STUDY TO ASSESS SAFETY, TOLERABILITY, AND CLINICAL EFFICACY OF AZD4547 IN PATIENTS WITH RELAPSED/REFRACTORY FGFR FUSION POSITIVE GLIOMA
Authors: Alberto Picca, Anna Luisa Di Stefano, Julien Savatovsky, Francois Ducray, Olivier Chinot, Elisabeth Cohen-Jonathan Moyal, Paule Augereau, Yohann Schmitt, Julie Lerond, Nabila Rousseaux, Christine Fardeau, Karima Mokhtari, Franck Bielle, David Meyronet, Antonio Iavarone, Marc Sanson
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND AZD4547 is a potent oral FGFR1-3 inhibitor. We tested its safety, tolerability, and efficacy in patients presenting relapsed/refractory (r/r) high-grade gliomas (HGGs) with FGFR fusion in a phase I/II open label multicenter study (NCT02824133). METHODS the study was based on a two-stage design and included adult patients with HGG expressing a FGFR-TACC gene fusion (as centrally confirmed by RT-PCR sequencing) relapsing after at least one line of standard chemoradiation. Patients received AZD4547 (AstraZeneca) at a dose of 80mg bd on a continuous schedule, until disease progression or inacceptable toxicity. The primary endpoint was the 6-months progression-free survival rate (PFS6). This research was conducted with support from AstraZeneca. RESULTS 12 patients with r/r isocitrate dehydrogenase wildtype HGGs positive for FGFR-TACC fusions (all FGFR3-TACC3) were included in the efficacy analysis cohort (male/female ratio = 1.4, median age = 61.5 years). Most patients (67%) were included at the first tumor relapse. The PFS6 was 25% (95% confidence interval [CI] 5-57%), with a median PFS of 1.4 months. All patients without progression at six months (n = 3) were at the first tumor recurrence (versus 56% of those in progression) and remained progression-free for 14-23 months. The best response was stable disease in six patients and progressive disease in six. Median OS was 17.5 months. Grade 3 toxicities included hematological, metabolic, nail changes, stomatitis, or other disorder (n = 1 each). No grade 4 toxicities were seen. CONCLUSION overall, tolerance was acceptable. The study did not meet the predetermined objective of PFS6 ≥ 35% and was stopped. A molecular characterization is ongoing to identify potential markers associated with prolonged stabilizations.
NCMP-14. HIGH GLIOMA PROLIFERATION SIGNIFICANTLY CORRELATES WITH LANGUAGE DEFICITS REGARDLESS OF MRI LESION SUBTYPE
Authors: Abraham Dada, Alexander Aabedi, Jasleen Kaur, EunSeon Ahn, David Brang, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND We recently demonstrated that glioma-infiltrated cortex engages in task-specific computations but may encode less information while doing so. The mechanistic underpinnings of glioma burden and its behavioral impact remains unknown OBJECTIVE To investigate the relationship between glioma burden and degree of cognitive impairments. METHODS One-hundred-eight patients with newly diagnosed WHO 2-4 diffuse glioma were recruited from a UCSF prospective registry. MRI FLAIR and T1 post-gadolinium tumor volume masks were demarcated. A “Composite” mask was generated from the sum of T1 post-gadolinium and FLAIR volume masks. Participants completed language assessments using the Quick Aphasia Battery (QAB). Glioma burden was determined by tumor-specific marker expression (IDH-1 mutation and P53) and glioma proliferation (Ki-67 and MIB-1 proliferation index). For each mask type, support-vector regression voxel-lesion symptom mapping (SVR-LSM) and linear regression analyses were performed to identify anatomic regions of interest (ROI) and glioma-specific factors associated with lower QAB scores. RESULTS SVR-LSM analysis by mask type revealed significant clusters in the left superior temporal gyrus: composite lesions within a cluster of 41,762 voxels and T1 post-gadolinium lesions within a cluster of 42,570 voxels. Both were independently predictive of lower QAB scores. SVR-LSM analysis of FLAIR masks failed to produce any significant clusters. Multivariate linear regression analysis of composite lesions was utilized to control for composite lesion voxel volume, glioma grade, and tumor-specific marker expression. The presence of voxels overlapping with the composite lesion ROI scores (beta = -0.13; p &amp;lt; 0.001), and, relative to a low glioma proliferation group (&amp;lt; 2%), glioma proliferation between 31-50% (beta = -2.00, p = 0.044) were independently and significantly predictive of lower QAB scores. CONCLUSION Relative to a low glioma proliferation group (&amp;lt; 2%), glioma proliferation between 31-50% significantly predicts language impairments, with a linear relationship between voxel overlap with ROI and impairment severity.
NIMG-43. A 57-YEAR-OLD MALE WITH PRIMARY GLIOBLASTOMA TREATED WITH LASER INTERSTITIAL THERMAL THERAPY: IMAGING AND AUTOPSY FINDINGS
Authors: Allison Lowman, Aleksandra Winiarz, Samuel Bobholz, Savannah Duenweg, Margaret Stebbins, Michael Flatley, Biprojit Nath, Fitzgerald Kyereme, Dylan Coss, Max Krucoff, Jennifer Connelly, Peter LaViolette
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION: Glioblastoma (GBM) is an aggressive primary brain cancer with significant resistance to the current therapeutic approach of chemotherapy and radiotherapy, jointly known as chemoradiation (CRT). Magnetic hyperthermia therapy (MHT) is a promising therapy for GBM that can be used to perform multiple sessions of non-invasive, localized hyperthermia by activating locally delivered magnetic iron oxide nanoparticles (MIONPs) with an external alternating magnetic field (AMF). In this study, MHT-mediated enhancement of CRT was evaluated in murine and human glioma cell lines both in cell culture and in rodents.